Acta Neurochir Suppl (2007) 97(2): 293–309 # Springer-Verlag 2007 Printed in Austria Electrical stimulation and gene-based neuromodulation for control of medically-refractory epilepsy A. V. Alexopoulos 1 , V. Gonugunta 3 , J. Yang 2 , and N. M. Boulis 2;3 1 Department of Neurology, Section of Adult Epilepsy, Cleveland Clinic Foundation, Cleveland, USA 2 Center for Neurological Restoration, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, USA 3 Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, USA Summary The failure of available antiepileptic medications to adequately con- trol seizures in a substantial number of patients underscores the need to develop novel epilepsy therapies. Recent advancements in technology and the success of neuromodulation in treating a variety of neurological disorders have spurred interest in exploring promising therapeutic alter- natives, such as electrical stimulation and gene-based synaptic control. A variety of different stimulation approaches to seizure control targeting structures in the central or peripheral nervous system have been inves- tigated. Most studies have been based on uncontrolled observations and empirical stimulation protocols. Today the vagus nerve stimulator is the only FDA approved adjunctive treatment for epilepsy that utilizes electrical stimulation. Other potential strategies including direct stimula- tion of the epileptogenic cortex and deep brain stimulation of various targets are currently under investigation. Chronically implanted devices for electrical stimulation have a variety of limitations. First, they are susceptible to malfunction and infection. Second, most systems require battery replacement. Finally, electrical stimulation is incapable of manipulating neuronal function in a transmitter specific fashion. Gene delivery to epileptogenic targets or targets implicated in regulating seizure threshold has been investigated as an alternative means of neuro- modulation in animal models. In summary, positive preliminary results and the lack of alternative treatment options provide the impetus for further exploration of electrical stimulation and gene-based therapies in pharmacoresistant epilepsy. Various specific targets and approaches to modulating their activity have been investigated in human studies. Keywords: Neuromodulation; gene therapy; epilepsy; seizures; elec- trical stimulation; review. Abbreviations AAV Adeno-associated virus, AdLC adenoviral vector expressing LC, AEDs antiepileptic drugs, ANT anterior nucleus of thalamus, BFNC benign familial neonatal convulsions, BPS bursts of pulse stimula- tion, CM centromedian (nucleus of thalamus), CNS central nervous system, CT computed tomography, DBS deep brain stimulation, EEG electroencephalogram, FDA food & drug administration, GPi globus pallidus internus, HSV herpes simplex virus, Kir inwardly rectifying potassium channels, LC light chain, MIE medically intractable epilepsy, MRI magnetic resonance imaging, SNr substantia nigra, pars reticulate, STN subthalamic nucleus, rTMS repetitive transcranial magnetic stimulation, TMS transcranial magnetic stimulation, TNS trigeminal nerve stimulation, VNS vagus nerve stimulation. Introduction Epilepsy, characterized by the repeated occurrence of unprovoked seizures, is one of the most common neuro- logical disorders with an estimated prevalence of 5–8 per 1000 population in developed countries. A large epi- demiologic study in the United States (Rochester, MN) showed an age-adjusted epilepsy prevalence of 6.8 per 1000 population, and a cumulative incidence through age 74 of 3.1% [17, 18]. Epilepsy exacts an enormous toll on patients and their families, while the loss of employment potential and cost of medical care has a substantial impact on society. Despite many decades of research, new antiepileptic drugs (AEDs), and advances in surgical therapy, a large number of people with epi- lepsy suffer from incompletely controlled seizures or the side effects of drugs or surgical treatment [27]. For these medically refractory patients, current approaches to treatment will, at best, lessen but not prevent the oc- currence of seizures. Recent studies have indicated that approximately two thirds of patients with newly diag- nosed epilepsy will experience good seizure control with the first or second AED administered [21, 22]. Almost one out of three patients, however, will have difficult-to- control epilepsy with frequent, disruptive seizures and undesirable medication-related side effects. Medically intractable epilepsy (MIE) is often a chronic, lifelong problem associated with a poor quality of life, constant